Panobinostat in combination with rituximab in heavily pretreated diffuse large B-cell lymphoma: Results of a phase II study.

This is a phase II study of panobinostat, an oral pan-HDAC inhibitor, combined with rituximab in patients with relapsed diffuse large B cell lymphoma. Panobinostat was administered orally 3 times a week every other week on a 28-day cycle. Rituximab was administered weekly during the first cycle, then on Day 1 of cycles 2 to 6. Patients without disease progression after 6 cycles continued panobinostat monotherapy for up to 6 additional cycles in the absence of disease progression. Eighteen eligible subjects were enrolled, and 18 were evaluable for response. The overall response rate was 11% (90% CI [2%-34%]) with 2 subjects having a partial response. The duration of response in these subjects was 51 and 60 days. Five additional subjects had stable disease with 3 subjects having tumor reduction between 27 and 44%, not meeting criteria for partial response. One subject with stable disease remained on therapy a total of 12 cycles. The most common toxicities while on study were thrombocytopenia (14 patients, 78%); fatigue (11, 61%); anemia (10, 56%); diarrhea (8, 44%); and nausea, lymphopenia, anorexia, and hypophosphatemia (5 each, 28% of patients), the majority of which was grade 2 or less. These data indicate that the combination of panobinostat with rituximab is able to induce responses in a limited number of subjects with relapsed diffuse large B cell lymphoma.

Ibrutinib maintenance after frontline treatment in patients with mantle cell lymphoma.

Maintenance rituximab in mantle cell lymphoma (MCL) has improved survival and supports exploration of maintenance with novel agents. We evaluated the safety and efficacy of ibrutinib maintenance (I-M) after induction in patients with treatment-naive MCL. Patients with MCL with complete response (CR) or partial response to frontline chemoimmunotherapy ± autologous stem cell transplantation (auto-SCT) received I-M 560 mg daily for up to 4 years. Primary objective was 3-year progression-free survival (PFS) rate from initiation of I-M. Minimal residual disease (MRD) assessments by next-generation sequencing (NGS) on peripheral blood were measured before I-M initiation and at 1, 6, and 18 to 24 months after initiation. Among 36 patients, the median age was 60 years (range, 46-90). For frontline treatment, 18 patients (50%) had consolidation with auto-SCT in CR1 before I-M. At median follow-up of 55.7 months, 17 patients (47%) completed full course I-M (median, 37.5 cycles; range, 2-52). The 3-year PFS and overall survival (OS) rates were 94% and 97%, respectively. With prior auto-SCT, 3-year PFS and OS rates were both 100%. The most common treatment-related adverse event with I-M was infection (n = 31; 86%), typically low grade; the most common grade 3/4 toxicities were hematologic. In 22 patients with MRD assessments, all were MRD negative after induction. Six became MRD positive on I-M, with 2 reverting to MRD-negative status with continued I-M, and all maintain radiographic CR with the exception of 1 with disease progression. I-M is feasible in MCL after frontline chemoimmunotherapy with manageable toxicities although significant. Changes in NGS-MRD were noted in limited patients during maintenance with few progression and survival events. This trial was registered at www.clinicaltrials.gov as #NCT02242097.

Brentuximab vedotin plus doxorubicin and dacarbazine in nonbulky limited-stage classical Hodgkin lymphoma.

ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) with or without radiation has been the standard treatment for limited-stage Hodgkin lymphoma (HL) but carries risks of bleomycin lung injury and radiation toxicity. Brentuximab vedotin (BV) is approved with AVD for stage III-IV HL, but carries increased risks of peripheral neuropathy (PN) and neutropenic fever, likely due to overlapping toxicity between BV and vinblastine. We therefore evaluated BV in combination with AD for 4 or 6 cycles based on interim positron emission tomography response. Thirty-four patients with nonbulky stage I-II HL were enrolled. Risk was early favorable in 53% and unfavorable in 47%. The overall and complete response rates (CRRs) were 100% and 97%, respectively, with a 5-year progression-free survival (PFS) of 91%. No differences in outcome were observed based on stage (I vs II) or risk status (early favorable vs unfavorable). The most common adverse events were nausea (85%), peripheral sensory neuropathy (59%), and fatigue (56%). There were no cases of grade-4 neutropenia or neutropenic fever, and no patient received granulocyte-colony stimulating factor. Most cases of PN were grade 1, and no patient experienced grade ≥3 PN. BV-AD produced a high CRR and durable PFS with most patients requiring 4 cycles of therapy. Compared with BV-AVD, the toxicity profile appeared improved, with predominantly grade 1 reversible PN and no case of grade 4 neutropenia or neutropenic fever. This regimen warrants further study in HL and may serve as a backbone for the addition of novel agents. This trial is registered on clinicaltrials.gov (NCT02505269).

Zanubrutinib, obinutuzumab, and venetoclax with minimal residual disease-driven discontinuation in previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: a multicentre, single-arm, phase 2 trial.

BACKGROUND: We hypothesised that combining zanubrutinib with obinutuzumab and venetoclax (BOVen) as an initial therapy for chronic lymphocytic leukaemia and small lymphocytic lymphoma would lead to high rates of undetectable minimal residual disease (MRD), and we explored MRD as a biomarker for directing treatment duration. METHODS: This multicenter, investigator-initiated, single-arm, phase 2 trial took place at two two academic medical centres in the USA. Patients were eligible for the primary cohort if they had treatment-naive chronic lymphocytic leukaemia or small lymphocytic lymphoma, required therapy, and were at least 18 years of age with an Eastern Cooperative Oncology Group performance status up to 2. BOVen was administered in 28 day cycles (oral zanubrutinib at 160 mg twice per day starting in cycle 1 on day 1; intravenous obinutuzumab at 1000 mg on day 1 [split over day 1 with 100 mg and day 2 with 900 mg for an absolute lymphocyte count >25 000 cells per µL or lymph nodes >5 cm in diameter], day 8, and day 15 of cycle 1, and day 1 of cycles 2-8; and oral venetoclax ramp up to 400 mg per day starting in cycle 3 on day 1) and discontinued after 8-24 cycles when prespecified undetectable MRD criteria were met in the peripheral blood and bone marrow. The primary endpoint was the proportion of patients that reached undetectable MRD in both the peripheral blood and bone marrow (flow cytometry cutoff less than one chronic lymphocytic leukaemia cell per 10 000 leukocytes [<10-4]) assessed per protocol. This trial is registered at clinicaltrials.gov (NCT03824483). The primary cohort is closed to recruitment, and recruitment continues in the TP53-mutated mantle cell lymphoma cohort. FINDINGS: Between March 14, 2019, and Oct 10, 2019, 47 patients were screened for eligibility, and 39 patients were enrolled and treated. Median age was 62 years (IQR 52-70) with 30 (77%) of 39 male participants and nine (23%) of 39 female participants. 28 (72%) of 39 patients had unmutated immunoglobulin heavy-chain variable-region and five (13%) of 39 had 17p deletion or TP53 mutation. After a median follow-up of 25·8 months (IQR 24·0-27·3), 33 (89%) of 37 patients (95% CI 75-97) had undetectable MRD in both blood and bone marrow, meeting the prespecified undetectable MRD criteria to stop therapy after a median of ten cycles (IQR 8-12), which includes two cycles of zanubrutinib and obinutuzumab before starting venetoclax. After median surveillance after treatment of 15·8 months (IQR 13·0-18·6), 31 (94%) of 33 patients had undetectable MRD. The most common adverse events were thrombocytopenia (23 [59%] of 39), fatigue (21 [54%]), neutropenia (20 [51%]), and bruising (20 [51%]), and the most common adverse event at grade 3 or worse was neutropenia (seven [18%]) in the intention-to-treat population. One death occurred in a patient with intracranial haemorrhage on day 1 of cycle 1 after initiating intravenous heparin for pulmonary emboli. INTERPRETATION: BOVen was well tolerated and met its primary endpoint, with 33 (89%) of 37 previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma reaching undetectable MRD in both peripheral blood and bone marrow despite a median treatment duration of only 10 months, owing to our undetectable MRD-driven treatment discontinuation design. These data support further evaluation of the BOVen regimen in chronic lymphocytic leukaemia and small lymphocytic lymphoma with treatment duration guided by early MRD response kinetics. FUNDING: Beigene, Genentech (Roche), Grais-Cutler Fund, Lymphoma Research Fund, Lymphoma Research Foundation, American Cancer Society, Farmer Family Foundation, and the National Instititutes of Health and National Cancer Institute.

Oral fludarabine has significant activity in patients with previously untreated chronic lymphocytic leukemia, and leads to increased STAT1 levels in vivo.

Fifteen patients with previously untreated chronic lymphocytic leukemia (CLL) were treated with oral fludarabine. Toxicities were mainly hematologic, and the response rate was 80%. To assess the effect of fludarabine on the transcription factor STAT1, blood samples obtained on study entry were treated in vitro with fludarabine for 24 h, and the majority of samples displayed an expected decrease in STAT1. To determine whether similar changes occurred in vivo, we developed a flow cytometric assay to quantitate STAT1 levels. On completion of fludarabine cycle 1, CLL cells showed increased STAT1 in the majority of patients, in contrast to the in vitro findings. This may reflect a survival advantage for cells that express high levels of STAT1. In conclusion, oral fludarabine is highly active and merits further investigation in previously untreated patients with CLL. Larger studies are indicated to determine optimal timing of STAT1 assessment, and if changes in STAT1 represent an in vivo indicator of response to purine analog therapy.

FDG-PET is superior to gallium scintigraphy in staging and more sensitive in the follow-up of patients with de novo Hodgkin lymphoma: a blinded comparison.

Accurate staging of Hodgkin lymphoma (HD) allows for minimization of therapy and reduction of long-term toxicities. The present study prospectively compares FDG-PET with gallium/SPECT scintigraphy at time of diagnosis and in follow-up of 36 patients with HD. Prior to therapy, whole body FDG-PET and gallium/SPECT were performed. Follow-up scans were obtained after 3 cycles of chemotherapy (n = 22), and at the end of chemotherapy (n = 32). Two nuclear medicine physicians independently interpreted scans in blinded and random order and a consensus was obtained. Baseline scans revealed a greater number of supradiaphragmatic disease sites detected by PET, and 5 patients had splenic involvement on PET not noted by gallium (P = 0.05); 3 patients were upstaged on PET. Midway through therapy, 5 patients had positive PET (4 of whom relapsed), and 3 had positive gallium (1 relapsed). At conclusion of chemotherapy, 8 patients had a positive PET (4 relapsed) and 3 had a positive gallium (2 relapsed). In conclusion, diagnostic PET and gallium are largely concordant, with the exception of unique detection of splenic disease by PET. However, more patients have persistently positive PET at the end of chemotherapy compared with gallium (P = 0.04), although only half of these patients have relapsed.

Autologous bone marrow transplantation for marginal zone non-Hodgkin's lymphoma.

The marginal zone non-Hodgkin's lymphomas are a recently defined group of related low-grade B cell malignancies whose natural history is heterogeneous. The optimal therapy is often unclear, particularly for the subset of patients with disseminated disease that behaves aggressively. We have retrospectively analyzed the outcomes of 11 patients with chemosensitive but disseminated marginal zone lymphomas who underwent uniform conditioning with cyclophosphamide and total body irradiation followed by bone marrow transplantation (BMT) with anti-B cell monoclonal antibody-purged autologous bone marrow between January 1994 and September 1999. All patients had stage IV disease and received multiple chemotherapy regimens prior to autologous BMT. Only 36% were in complete remission at the time of bone marrow harvest, and 36% had overt bone marrow infiltration at that time. Two treatment-related deaths occurred between 100 days and 6 months. Three patients relapsed and died of disease. One patient developed and died of myelodysplasia. Five patients remain in continuous complete remission at a median follow-up of 52 months (45%). The median progression-free survival for these patients was 56 months, with median overall survival 58 months. The only significant predictor of disease-free and overall survival was age at the time of transplant; no patient under 45 at the time of transplant has relapsed or died of any cause (P = 0.003). Outcomes of autologous BMT in patients with disseminated marginal zone NHL are similar to those in follicular NHL, and suggest that certain patients may experience prolonged disease-free survival.

Phase II study of dasatinib in relapsed or refractory chronic lymphocytic leukemia.

PURPOSE: Chronic lymphocytic leukemia (CLL) cells treated with dasatinib in vitro undergo apoptosis via inhibition of Lyn kinase. Thus, in this study we tested the activity of dasatinib in patients with relapsed CLL. EXPERIMENTAL DESIGN: Patients were eligible for this phase II trial if they had documented CLL/SLL and had failed at least 1 prior therapy with a fludarabine-containing regimen and if they required therapy according to NCI-WG criteria. The starting dose of dasatinib was 140 mg daily. RESULTS: Fifteen patients were enrolled, with a median age of 59 and a median of 3 prior regimens. All patients had received fludarabine, and 5 were fludarabine-refractory. Eleven of the 15 (73%) had high risk del(11q) or del(17p) cytogenetics. The primary toxicity was myelosuppression, with grade 3 or 4 neutropenia and thrombocytopenia in 10 and 6 patients, respectively. Partial responses by NCI-WG criteria were achieved in 3 of the 15 patients (20%; 90% CI: 6-44). Among the remaining 12 patients, 5 had nodal responses by physical exam, and 1 patient had a nodal and lymphocyte response but with severe myelosuppression. Pharmacodynamic studies indicated apoptosis in peripheral blood CLL cells within 3 to 6 hours after dasatinib administration, associated with downregulation of Syk (spleen tyrosine kinase) mRNA. CONCLUSIONS: Dasatinib as a single agent has activity in relapsed and refractory CLL.

Intravenous methotrexate as central nervous system (CNS) prophylaxis is associated with a low risk of CNS recurrence in high-risk patients with diffuse large B-cell lymphoma.

BACKGROUND: The outcome of patients with systemic diffuse large B-cell lymphoma (DLBCL) had improved over the past decade with the addition of monoclonal antibody therapy. Unfortunately, approximately 5% of these patients still developed a secondary central nervous system (CNS) recurrence followed invariably by rapid death. This rate is substantially increased in patients with certain high-risk features. Although prophylaxis against CNS recurrence with either intrathecal or intravenous methotrexate is commonly used for such patients, to the authors' knowledge, there is no standard of care. Retrospectively evaluated was the role of high-dose systemic methotrexate combined with standard cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab (R-CHOP) chemotherapy to decrease CNS recurrence in high-risk patients. METHODS: A total of 65 patients with DLBCL and CNS risk factors were identified at the study institution between 2000 and 2008 who received intravenous methotrexate as CNS prophylaxis concurrent with standard systemic therapy with curative intent. CNS recurrence rate, progression-free survival, and overall survival were calculated. RESULTS: Patients received a median of 3 cycles of methotrexate at a dose of 3.5 gm/m(2) with leucovorin rescue. The complete response rate was 86%, with 6% partial responses. At a median follow-up of 33 months, there were only 2 CNS recurrences (3%) in this high-risk population. The 3-year progression-free and overall survival rates were 76% and 78%, respectively. Complications associated with methotrexate therapy included transient renal dysfunction in 7 patients and a delay in systemic chemotherapy in 8 patients. CONCLUSIONS: Intravenous methotrexate can be safely administered concurrently with R-CHOP and is associated with a low risk of CNS recurrence in high-risk patients.

Gemcitabine added to doxorubicin, bleomycin, and vinblastine for the treatment of de novo Hodgkin disease: unacceptable acute pulmonary toxicity.

BACKGROUND: Gemcitabine is an effective treatment for recurrent Hodgkin disease (HD), with relatively minimal associated toxicity. The authors conducted a trial substituting this drug for dacarbazine in the standard regimen to form ABVG (doxorubicin, bleomycin, vinblastine, gemcitabine) for patients with newly diagnosed, high-risk HD. METHODS: Twelve patients (median age, 34 years) with advanced-stage de novo HD were enrolled. Standard doses of doxorubicin, bleomycin, and vinblastine were given for six cycles. Cohorts of three patients were enrolled and the dose of gemcitabine was escalated to identify the maximally tolerated dose in this combination. RESULTS: The maximally tolerated dose of gemcitabine was determined to be 800 mg/m(2) in this combination. Five patients developed clinically significant pulmonary toxicity. Three required hospitalization during the final two cycles of treatment. Pneumonitis could not be predicted with serial diffusion capacity for carbon monoxide (DECO) evaluations, and reversed after discontinuation of bleomycin in three patients and steroid therapy in two patients. All 12 patients are alive to date, and 4 patients have experienced disease progression. CONCLUSIONS: The bleomycin/gemcitabine combination should not be pursued for de novo HD due to significant pulmonary toxicity.